New series of organic compounds



United States Patent 6 NEW SERIES OF ORGANIC COMPOUNDS Werner R. Boehme, Somerville, and Joseph Nichols, Princeton, N.J., assignors to Ethicon, Inc, a corpora tion of New Jersey N Drawing. Application October 24, 1957 Serial No. 692,958

18 Claims. (Cl. 260-3263) is attached to any one of the ring carbon atoms, including the bridge member, of the bicyclic ring. Di-substituted compounds are those having at least one ring quaternary carbon at'the 2, 3', 5, 6, 7 or 8 positions of the bicyclic ring wherein the two available valencesv of the quaternary carbon atom are attached to (a) the radical and (b) the radical R, representing a lower hydrocarbon radical. Also included within the scope of this invention arethe corresponding therapeutically active addition salts and quaternary ammonium compounds.

The novel compounds may be representedbythe following general structural formula:

1 wherein Z is an ethylene or vinylene radical, Y isa methylene or ethylene radical, R and R are, interchangeably,

hydrogen atoms or lower hydrocarbon radicals containing from 1 to 7 carbon atoms such as alkyl, as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, pentyl, isopentyl, secondary pentyl, hexyl or isohexyl; or alkenyl, as for example allyl, a-methylallyl or B-methyl-allyl; X is a lower alkylene or lower alkylidene radical containingfrom 1 to 7 carbon atoms, such as for example methylene, ethylene, propylene, isopropylene, butylene, isobutylene, pentylene, isopentylene, hexylene, iso-hexylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, pentylidene, isopcntylidene, hexylidene or isohexylidene; and R is a secondary or tertiary amino group, attached to X by a carbon to nitrogen bond, as for example lower hydrocarbonamino, the lower hydrocarbon function being a saturated or unsaturated, cyclic, straight or branch-chained 'alkyl group containing from 1 to '7 cmbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, cyclohexyl, allyl, benzyl, etc; or an N, N-dilower hydrocarbonamino, the lower hydrocarbon function being a saturated or unsaturated, cyclic, straight or branch-chained alkyl group as. defined aboye,,or an 2,926,172 Patented Feb. 23, 1960 N, N-lower alkylene-amino group, the alkylene chain of which contains from 4 to 6 carbon atoms, which are in the form of a straight carbon chain or interrupted by one or more hetero atoms such as oxygen, sulfur or nitrogen, thus forming a lower oxa-, thiaor aza-alkylene radical and which, when taken together with the nitrogen atom may form, for example, a piperidino, pyrrolidino, hexamethyleneimino, morpholino, thiamorpholino or piper azino radical.

Acid addition salts of the compounds of this invention are those obtainable by. reaction with organic or inorganic acids and yielding therapeutically active compounds, as for example, hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acid; sulfuric, nitric, thiocyanic, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, salicylic, p-amino-salicylic, Z-phenoxy-benzoic acid, Z-acetoxy-benzoic acid, etc.

Quaternary ammonium compounds of this invention having the above general structural, formula are lower alkyl halogenides such as methiodides, ethobromides or propylchlorides; lower-alkenyl halogenides such as allyl bromides; lower alkyl sulfates such as dimethylsulfates or diethylsulfates, and the corresponding hydroxides.

The substituent groups on the bicyclic nuclei may be spatially related in what is known as exo or endo positions. The following structural formula shows the spatial relationships of the exo and endo positions of the substituent groups on a bicycloheptene nucleus, cor,- responding spatial relationships being applicable to the bicyclo-heptane and bicyclooctene nuclei.

I Exo Endo The compounds of this invention have utility in the treatment of cardiac arrhythmias because of their marked anti-arrhythmic and anti-fibrillatory activity.

Quim'dine sulfate and Z-endo-(diethylaminoacetamino)- bicyclo-(2,2,1)-heptane hydrochloride were each tested for ability to shorten auricular arrhythmia according to the following procedurevin which six dogs were used for each substance tested. Auricular arrhythmias were induced. in anesthetized, open-chest dogs by applying pledgets soaked with 5%: methocholine chloride aqueous solution to the sinus node region accompanied by mechanical, pinching of, the auricular wall. The duration of the arrhythmia was observed and then reinduced in the same manner and the duration was again observed. The arrhythmia was induced and then five milligrams perkilogram of'body weight of afive-tenths percent by weight solution of the compound to be testedin physiological saline solution was injected intravenously at once to kill fifty percent of the mice to which quinidine sulfate and 2-endo-(diethylaminoacetamino)-bicyclo-(2,2, 1)-heptane hydrochloride were administered intraperitoneally was 202 and 340 milligrams per kilogram of body weight, respectively.

The novel compounds of this invention may be prepared by reacting a suitable bicyclic primary or secondary amine with a haloacyl halide followed by treatment of the resulting haloamide with a primary or secondary amine such as an alkylamine, aralkylamine or dialkylamine; pyrrolidine or piperidine. If desired, the haloamide may be prepared by reacting the bicyclic primary amine with a bis-haloacyl anhydride.

An alternative and equally suitable method for pre paring the compounds of this invention includes direct acylation of the bicyclic primary amine with the appropriately substituted aminocarboxylic acid halide. Still another method includes the reaction between the unsubstituted bicyclic ring, e.g. bicyclo-(2,2,1)-heptene, and the appropriately substituted amino alkano nitrile.

Inorganic salts of the compounds of this invention may be prepared by passing the acid in gaseous form into an ether solution of the amides or by adding the amide or an alcohol solution of the amide to an alcohol solution of the inorganic acid. The salt is obtained by evaporation of the solution and recrystallization from a mixture of alcohol and ether. Organic acid salts are prepared by mixing. an alcohol solution of the amide with an alcohol solution of the organic acid. The alcohol is evaporated, preferably under reduced pressure, and the salt is recrystallized from a mixture of alcohol and ether.

Quaternary ammonium compounds may be prepared by reacting the tertiary bases with an ester formed by a hydroxylated lower hydrocarbon compound with a strong inorganic or organic acid. Such esters are, for example, lower alkyl halides such as methyliodide, ethylbromide or propylchloride; lower alkenyl halides such as allyl bromide; aralkyl halides such as benzyl chloride; dilower alkyl sulfates such as dimethylsulfate or diethylsulfate, or lower alkyl arylsulfonates such as methyl ptoluol sulfonate. Alternatively, the quaternary ammonium compounds may be prepared by reacting the intermediate haloamides with a tertiary amine such as triethylamine, dimethylbenzylamine or pyridine.

The quaternizing reaction may be performed in the presence or absence of a solvent, at room or elevated temperature or at a subnormal temperature. It may be conducted at atmospheric pressure or in a closed reaction vessel under pressure.

Suitable solvents for conducting the quaternization reaction are lower alkanols, ketones or ethers, such as methanol, ethanol, propanol, isopropanol, amyl alcohol, acetone, cyclohexanone, diethylether or tetrahydrofurane. When the quaternization is carried out with lower halogenides, dimethylformamide and formamide may advantageously be used as solvents, the reaction being suitably conducted in a closed vessel under pressure.

Quaternary ammonium compounds obtained as described above may be suitably converted into the corresponding quaternary ammonium hydroxides. For example, the quaternary ammonium halides may be reacted with silver oxide, the sulfates may be reacted with barium hydroxide or the quaternary salts may be reacted with an anion exchanger in the hydroxyl cycle. The resulting bases may be converted to therapeutically useful quaternary ammonium salts by reaction with organic or inorganic acids; for example, any of those mentioned hereinabove. The quaternary ammonium compounds may be converted to other quaternary salts directly without conversion with the quaternary hydroxide. For example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride to yield the quaternary ammonium chloride, or the quaternary ammonium iodide may be converted into the corresponding chloride by treatment with hydrochloric acid in anhydrous methanol.

Depending on the conditions employed, the novel compounds may be obtained either as free bases or as salts. The bases may be converted to salts by treatment with an acid such as one of those described above. The salts may be converted to free bases by treatment with an alkaline reagent such as sodium hydroxide.

Acylation of the amine is preferably performed in the presence of an acid neutralizing agent such as a liquid organic base; for example, pyridine, collidine or lutidine. Also suitable for this purpose are the alkali metal carbonates, for example sodium carbonate or potassium hydrogen carbonate. Although the organic base may also function as a diluent, other solvents such as benzene, toluene or hexane may be used for that purpose. The reaction may be carried at elevated temperatures. However, most satisfactory yields are obtained at room temperature, 20 C. to 25 C., or below.

In addition, it may be noted here that the compounds of this series where X is ethylene may be prepared by reacting a primary or secondary amine with a bicyclic acrylamide.

The following examples illustrate the preparation of the novel compounds, but they are not to be construed as limiting the spirit of the invention or its scope.

Example I 15.6 grams of chloracetyl chloride were added with stirring and cooling to a solution of 14.5 grams of 2- endoaminobicyclo-(2,2,l)-heptane, which had been prepared according to the method of Alder and Stein, Annalen der Chemie, volume 514, page 224 (1934), and 11.3 grams of pyridine in 75 cc. of dry benzene. The reaction mixture, which was in the form of a suspension, was, after having been allowed to stand for one hour, washed successively with water, dilute hydrochloric acid and finally with water. The benzene solution was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue consisted substantially of 2-endo-(chloracetamino)-bicyclo-(2,2,1)-heptane and was recrystallized from an aqueous ethanol solution and then from hexane. The recrystallized material had a melting point of IDS-106 C.

A solution of 9.8 grams of recrystallized 2-endo- (chloracetamino)-bicyclo-(2,2,1)-heptane and 8.4 grams of diethylamine in 30 grams of percent ethanol was heated in a sealed glass tube at C. for twelve hours. The reaction mixture, which was in the form of a suspension, was cooled, treated with aqueous sodium hydroxide solution, and the alkaline solution was shaken with benzene. The benzene solution was removed by distillation under reduced pressure. The residue was distilled and 2 endo (diethylaminoacetamino) bicyclo- (2,2,1)-heptane collected at 107-110" C. at 0.08 millimeters pressure, n 1.4875.

Gaseous hydrogen chloride was passed into a solution of the distilled 2-endo-(diethylaminoacetamino)-bicyclo- (2,2,1)-heptane in anhydrous ether. The hydrochloride salt precipitated from the ether solution and was purified by recrystallization from benzene and then from acetone. The recrystallized salt had a melting point of 194-195 C.

Example II Example III A solution of 18.8 g. of 2-endo-(chloracetamino)-bicyclo-(2,2,1)-heptane and 15.6 g. of pyrrolidine in 60 ml. of 95% ethanol was condensed and the product isolated pared as in Example I, melted at 199-200" C. after era-am A solution of 63.5 g. of alpha-chloropropionyl chloride in 50 ml. of anhydrous benzene was added to a solution of 55.5 g. of 2-endoaminobicyclo-(2,2,1)-heptane solution made alkaline with sodium hydroxide solution and the precipitated oil extracted with ether. The ether extracts were dried over anhydrous potassium carbonate and distilled under reduced pressure. 2-endo-(benzylaminoacetamino)-bicyclo-(2,2,1)-heptane was collected as a pale yellow liquid boiling at ZOO-210 ,C./0.05 arm,

and 45 g. of anhydrous pyridine in 350 ml. of anhydrous benzene during hour with stirring and cooling. Stirring was continued for one hour longer without cooling. The precipitated pyridine hydrochloride was removed by filtration and washed with benzene. The combined filtrates were then washed with dilute hydrochloric acid and again with water. Distillation of the filtrates on the steam bath under reduced pressure left a solid residue which gave colorless needles of 2-endo-(alpha-chloropropionylamino)bicyclo-(2,2,1)-hptane melting at 133- 134 C., after recrystallization from heptane.

Example V p A solution of 20.1 g. of 2-endo-(alpha-chloropropionylamino)-bicyclo-(2,2,1)-heptane and 16.1 g. of diethylamine in 60 ml. of 95% ethanol was condensed as in Example I. The resulting 2-endo-(alpha-diethylaminopropionylamino)-bicyclo-(2,2,1)-heptane was obtained as a colorless liquid boiling at 118-120" C./0.l5 mm., n 1.4863.

The hydrochloride prepared as in Example I melted at 167-168 C. when recrystallized from ethyl acetate.

Example VI A solution of 50 g. of 2-endomethyl-Z-exoaminobicyclo- (2,2,1)-heptane' hydrochloride (prepared according to Beckmann, et al. Ben, 87, 1001 (1954) in200 ml. of water was made alkaline with sodium hydroxide solution and the free amine was extracted with ether. The extracts were dried over solid potassium hydroxide and distilled. 2-endornethyl-2-exoaminobicyclo (2,2,1)-heptane Was obtained as a colorless liquid boiling at 163 C. which solidified on cooling.

A solution of 39.1 g. of chloracetyl chloride in 50 ml. of anhydrous benzene was added to a solutionof 43.3 g. of 2-endomethyl-2-exoaminobicyclo-(2,2,1)-heptane and 30.1 g. of anhydrous pyridine in 250 ml. of dry .ben-

' zene in hour with stirring and cooling. The mixture was stirred one hour longer without cooling and the precipitated pyridine hydrochloride was washed with benzene. The combined filtrates were washed with dilute hydrochloric acid and with water. The benzene was removed by distillation under reduced pressure on the steam bath and the residue was crystallized several times from heptane. 2-endomethyl 2-exo (chloracetamino)- bicyclo-(2,2,1)-heptane was obtained as colorless needles, melting at 83.5-84.5 C.

A solution of 20.1 g. of 2-endomethyl-2-exo(chloracetamino)bicyclo-(2,2,1)-heptane and 16.1 g. of diethylamine in 60 ml. of 95% ethanol was heated'in a sealed tube at 130 for 16 hours. The product which was worked up as in Example I distilled at 109-111" Chat 0.15 mm., n 1.4839. The hydrochloride (preparedas in Example I) was obtained as colorless needles melting at 173-1745" when recrystallized from ethyl acetate.

Example VII A mixture of 22.4 g. of 2-endo-(chloracetamino)bicyclo-(2,2,1)-heptane and 28.0 g. ofbenzylamine was heated at an oil bath temperature of 125'" C. for 12 hours, cooled, and dissolved in a solution of 12 ml. of concentrated] hydrochloric acid in 150 ml. of water. The solution was then allowed to crystallize in an icebath and the product removed by filtration. The crude hydrochloride was redissolved in 700 ml. of water, the

The hydrochloride, prepared as in Example I, was obtained as colorless glistening plates melting at 246-248 C. whenrecrystallized from water.

Example VIII 2-exoaminobicyclo-(2,2,1)-heptane (prepared according to Alder and Stein, Ann., 514, 224 (1934)) was converted to Z-exo (chloracetamino) bicyclo (2,2,1)- heptane melting at 126-127." C. by the procedure described for the endo-isomer in Example I.

2-exc-(diethylaminoacetamino) bicyclo (2,2,1)-heptane (prepared according to the procedure described for the endo-isomer in Example I)-was obtained as a colorless liqnid boiling at 112-116" C./0.05 mm. 11 1.4873.

The hydrochloride (prepared as in Example I) melted at,183,184.5 C. when recrystallized from toluene or methyl ethyl ketone.

Example IX A solution of 18.8 g. of 2-endo-(chloracetamino)- bicyclo-(2,2,1)-hep tane and 17.4 g. of Z-diethylaminoethylamine in 60 ml. of ethanol was condensed'as in Example I. The product, 2-endo-[(2-diethylaminoethyl) aminoacetamino] bicyclo (2,2,1)-heptane, obtained by distillation boiled at 171-176" C./0.15 mm.

The dihydrochloride prepared as in Example I melted at 217-219 C. when recrystallized from isopropanol.

Example X A solution of 18.8 g. of 2-endo-(chloracetamino)- rnicycl0-(2,2,1)-heptane and 9.9 g. of anhydrous dimethylamine in 60 ml. of 95% ethanol was condensed as in Example}. The product, Z-endo-(dimethylaminoacetamino)-bicyclo-(2,2,1) -heptane, which boiled at 87-89" C./0.03 mm., 11 1.4944 was converted to the hydrochloride as in Example I and melted at 238-240" .C. when recrystallized from acetone.

Example XI A solution of 18.8 g. of 2-endo-(chloracetamino)- bicyclo-(2,2,1)-heptane and 13.0 g. of isopropylamine in 60 ml. of 95% ethanol was condensed as in Example T. The product, 2-endo-(isopropylaminoacetamino)-bicyclo-(2,2,l)-heptane, which boiled at 112116 C./0.02 mm., 11 1.4933, was converted to the hydrochloride by the procedure described in Example I. The hydrochloride melted at 223-225" C. when recrystallized from isopropanol.

' Example XII 2-aminobicyclo-(2,2,2)-octane (prepared by the method of Seka and Tro-mposch, Ber. 75, 1381 (1942) was chloracctylated by the procedure described for Z-endoamino-bicyclo-(2,2,1)-heptane in Example I. The resulting 2-(chloracetamino)-bicyclo-(2,2,2)-octane melted at 129-130 C. when recrystallized from hexane.

- A solution of 21.5 g. of the above chloracetamide and 16.1 g. of diethylamine in 60 m1. of 95% ethanol was condensed as in Example I. The product, Z-(diethylaminoacetamino)-bicyclo-(2,2,2)-octane, which boiled at -125" C./ 0.02 mm., 11 1.49 13 was converted to the hydrochloride by the procedure described in Example I and melted at 198-200" C. when recrystallized from alcohol-ether.

Example XIII I 43.1 g. of freshly distilled chloral dissolved in SO-ml. of chloroform was added dropwise with stirring during one hour at C. to a solution of 38.2 g. of 2-endoaminobicyclo-(2,2,l)-heptane in 200 ml. of chloroform. The solution was stirred for 2 hours longer without cooling, allowed to stand overnight and distilled under reduced pressure. 2-endo-(formylamino) bic-yclo- (2,2,1)-heptane was collected as a colorless viscous oil boiling at 104-108 C./0.05 mm., r1 1.5077.

38.0 g. of the above formamide dissolved in 100 ml. of anhydrous ether was added dropwise with cooling and stirring during 1 hour to a suspension of 10.5 g. of lithium aluminum hydride in 400 ml. of anhydrous ether. The suspension was refluxed for 2 hours and the complex decomposed with water and sodium hydroxide solution. The ether layer was decanted, dried over solid potassium hydroxide and fractionated under reduced pressure. Z-endo-(methylamino) bicyclo (2,2,1)-heptane was collected as a colorless fuming liquid boiling at 7577 C./33 mm., 11 1.4731.

A sample of the base was converted to the hydrochloride in anhydrous ether solution with gaseous hydrogen chloride. The hydrochloride melted .at 193-194 C. when reprecipitated from alcohol with ether.

24.6 g. of chloracetyl chloride dissolved in 30 ml. of anhydrous benzene was added dropwise during hour with stirring and cooling to a solution of 26.5 g. of 2- endo-(methylamino)-bicyclo-(2,2,1)-heptane and 16.8 g. of pyridine in 300 ml. of dry benzene. The suspension was stirred for 2 hours longer without cooling. The precipitated pyridine hydrochloride was filtered and washed with benzene. The filtrates were distilled under reduced pressure and 2-endo-(N-methyl-N-chloracetamino)-bicyclo-(2,2,1)-heptane was collected as a colorless liquid, boiling at 120-122 C./0.15,mm., 71 1.5219.

A solution of 20.2 g. of the above chloracetamide and 16.1 g. of diethylamine in 60 ml. of 95% ethanol was condensed by the procedure described in Example I.

, 2-endo- [N-methyl-N-( diethylaminoacet) amino] -bicyclo- (2,2,1)-heptane boiling at 116-118. C./0.05 mm., n

1.4918, was collected and converted to the hydrochloride The hydrochloride melted at 193.5

as in Example I. 194.5 when recrystallized from methyl ethyl ketone.

Example XIV To a solution of 12.9 g. of bicyclo-(2,2,1)-heptane-1- carboxylic acid (prepared according to Whelan, Dissertation, Columbia Univ., 1952) in 75 ml. of chloroform and 26 ml. of concentrated sulfuric acid at 4045 C. was added 7.2 g. of sodium azide in 1 hour with stirring. The temperature was maintained at 45 C. for 2 hours longer with stirring and occasional cooling. The suspension was cooled in ice, 35 ml. of water was added and the layers were separated. The chloroform phase was washed with water and the combined aqueous solutions were made alkaline with sodium hydroxide solution. The precipitated oil was extracted with ether and the extracts were dried over solid potassium hydroxide. Distillation of the extracts under reduced pressure gave a colorless liquid, 1-aminobicyclo-(2,2,1)-heptane, boiling at 142-145 C. which solidified on cooling.

To a solution of 6.0 g. of 1-aminobicyclo-(2,2,1)-heptane in 5.25 g. of pyridine and 20 ml. of dry benzene was added a solution of 6.8 g. of chloracetyl chloride in 10 ml. of dry benzene during 15 minutes at 05 C. with stirring. Stirring was continued for one hour longer without cooling. The precipitated pyridine hydrochloride was filtered and washed with benzene. The combined filtrates were washed with dilute hydrochloric acid and with water. Distillation of the benzene solution under reduced pressure gave 1 (chloracetamino) -bicyclo (2,2,1)-heptane boiling at 108-112" C./0.4 mm., which solidified on cooling. The product was purified by crystallization from heptane and by sublimation in vacuo. It formed colorless needles melting at 115-116 C.

A solution of 2.7 g. of 1-(chloracetaminoybicyclo -(2,2,1)-heptane and 3.1 g. of diethylamine in 12 ml.

'174 C. when recrystallized from toluene.

Example XV A solution of 10.8 g. of bicyclo-(2,2,1)-heptane-7- carboxylic acid (prepared by the method of Kwart and Kaplan, J.A.C.S., 76, 4072 (1954)) in 60 ml. of chloroform and 22 ml. of concentrated sulfuric acid was treated with 6.0 g. of sodium azide by the procedure described for the l-isomer above. 7-aminobicyclo-(2,2,1)-heptane was obtained by distillation as a colorless liquid boiling at 147-152 C. which solidified on cooling.

To a solution of 4.8 g. of 7-aminobicyclo-(2,2,1)-hep tane in 4.35 g. of pyridine and 15 ml. of dry benzene was added a solution of 5.65 g. of chloracetyl chloride in 10 ml. of dry benzene during 15 minutes at 0.5 C. with stirring. Stirring was continued for one hour longer without cooling. The precipitated pyridine hydrochloride was filtered and washed with dilute hydrochloric acid and with water. Distillation of the benzene solution under reduced pressure gave 7-(chloracetamino)-bicyclo- (2,2,1)-heptane, boiling at 106-110 C./0.25 mm., as a colorless liquid which solidified on cooling. Recrystallization from heptane gave colorless, flufiy needles melting at 84-85 C.

A solution of 4.0 g. of 7-(chloracetamino)-bicyclo- (2,2,1)-heptane and 4.6 g. of diethylamine in 16 ml. of ethanol was heated in a sealed glass tube at C. for 16 hours. The resulting 7-(diethylaminoacetamino)- bicyclo-(2,2,1)-heptane, which was isolated as in Example I, boiled at 112115 C./0.25 mm., n 1.4862. The hydrochloride, prepared in anhydrous ether solution with gaseous hydrogen chloride, melted at 156-157 C. when recrystallized from toluene.

Example XVI A solution of 6.01 g. of 2-endo-(chloracetamino)-bicyclo-(2,2,1)-heptane and 4.15 g. of methylethylamine in 30 ml. of 95 ethanol was heated in a sealed tube at C. for a period of 16 hours. The solvent was then removed under reduced pressure, the residue taken up in dilute hydrochloric acid and washed with ether. The aqueous phase was then rendered alkaline with 50% aqueous sodium hydroxide and extracted with ether. After drying the combined ether extracts over anhydrous potassium carbonate, the solution was distilled and 2-endo- (methylethylaminoacetamino) -bicyclo (2,2,1) heptane was collected under reduced pressure. The product boiled at 83-85 C./0.03 mm., 11 1.4915. The bydrochloride, prepared as in Example I, melted at 187- 188 C., when recrystallized from toluene and acetone.

Example XVII A solution of 6.01 g. of 2-endo-(chloracetamino)- (2,2,l)-heptane and 7.1 g. of di-n-propylamine in 30 ml. of 95 ethanol was condensed and the product isolated as in Example XVI. Distillation gave 2-endo-(di-npropylaminoacetamino)-bicyclo-(2,2,1)-heptane, boiling at 99102 C./0.03 mm., 21 1.4836. The hydrochloride, prepared as in Example I, melted at 159.5-161.5 C., when recrystallized from toluene and ethyl acetate.

Example XVIII A solution of 6.01 g. of 2-(endochloracetamino)-bicyclo-(2,2,1)-heptane and 6.1 g. of ethyl-n-propylamine in 30 ml. of 95 ethanol was condensed and the product isolated as in Example XVI. Distillation gave 2-endo- (ethyl n propylaminoacetamino)-bicyclo-(2,2,1)-heptane, boiling at 110-119 C./0.04 mm., 11 1.4853.

The hydrochloride, prepared as in Example I, melted at 150.5-152.5 C., when recrystallized from toluene and ethyl acetate.

Example XIX A solution of 6.01 g. of 2-endo-(chloracetamino)-bicyclo-(2,2,1)-heptane and 6.1 g. of ethyl-i-propylamine in 30 ml. of 95% ethanol was condensed and the product isolated as in Example XVI. Distillation gave 2-endo- (ethyl i propylaminoacetamino) bicyclo-(2,2,1)-heptane, boiling at 110-114 C./0.04 mm., 11 1.4855. The hydrochloride, prepared as in Example I, melted at 188.5-190.5 C., when recrystallized from toluene.

Example XX A solution of 6.01 g. of Z-endo-(chloracetamino)-bicyclo-(2,2,1)-heptane and 7.1 g. of di-i-propylamine in 30 ml. of- 95% ethanol was condensed and the product isolated as in Example XVI. Distillation gave 2-endo- (di-i-propylaminoacetamino) bicyclo (2,2,1) heptane, boiling at 110-114 C./0.04 mm., n 1.4853. The hydrochloride, prepared as in Example I, melted at 157.5- 158.5 0., when recrystallized from toluene.

Example XXI 47.8 g. of beta-chloropropionyl chloride dissolved in 35 ml. of dry toluene is added dropwise with stirring to a solution of 39.7 g. of 2-endoamino-bicyclo-(2,2,1)-heptane and 30.2 g. of dry pyridine in 130 ml. of dry toluene at 10-0 C. The mixture is worked up as in Example I, resulting in a product which on recrystallization from hexane yields colorless crystals of 2-endo-(beta-chloropropionylamino)-bicyclo (2,2,1) heptane, M.P. 98.5- 99 C.

A solution of 22.5 g. of 2-endo-(beta-chloropropionylamino)-bicyclo-(2,2,1)-heptane, 0.1 g. hydroquinone and 24.6 g. of diethylamine in 110 ml. of 95% ethanol is worked up as in Example I. The residue, on distillation, gives a liquid (which solidifies on cooling), Z-endo-(betadiethylaminopropionylamino)-bicyclo (2,2,1) heptane, B.P. 133-135 C. at 0.08 mm. and which is converted to the hydrochloride as in Example I, M.P. 140142 C.

Example XXII A solution of 12.8 g. of chloracetyl chloride in 20 ml. dry benzene was added dropwise in a half hour at --10-0 C. with stirring to a solution of 11.8 g. of endoamino-bicyclo-(2,2,1)-2-heptene prepared by the method of Parham et al., J.A.C.S. 73, 5069 (1951), and 9.4 g. of dry pyridine in 125 ml. of dry benzene. The mixture was stirred 2 hours longer without cooling. The precipitate was filtered, washed with benzene and the combined filtrates were washed with dilute hydrochloric acid and water. Distillation of the benzene solution under reduced pressure gave a liquid which solidified in the condenser, B.P. 92-96 C. at 0.08 mm. Several recrystallization from heptane gave colorless needless of S-endo- (chloracetamino)-bicyclo-(2,2,1)-2-heptene, M.P. 79- 81 C.

A solution of recrystallized 5-endo-(chloracetamino)- bicyclo-(2,2,1)-2-heptene and 8.0 g. of diethylamine in 30 ml. of 95% ethanol was condensed by the procedure described in Example I. S-endo-(diethylaminoacetamino)-bicyclo-(2,2,1)-2-heptene was collected at 122- 10 126 C./1 mm., n 1.4908, and converted to the hydrochloride as in Example I, M.P. 148.5- C.

What is claimed is: 1. A member selected from the group consisting of compounds represented by the general formula:

wherein Z is a member selected from the group consisting of ethylene and vinylene, Y is a member selected from the group consisting of methylene and ethylene, X is a member selected from the group consisting of lower alkylene and lower alkylidene, R and R are members of the group consisting of a hydrogen atom and saturated lower hydrocarbon radicals, and R is a member selected from the group consisting of N,N-di-lower alkylamino, piperidino, pyrrolidino, hexamethyleneimino, morpholino, thiamorpholino, piperazino and benzylamino attached to X by a carbon to nitrogen bond, the acid addition salts and lower alkyl quaternary ammonium salts thereof.

2. 2 endo (diethylaminoacetamino) bicyclo- (2,2,1)-heptane.

3. 2 endo (diethylaminoacetamino) -bicyclo-(2,2,1)- heptane methiodide.

4. 2 endo [(1 pyrrolidyl) acetaminol bicyclo- (2,2,1)-heptane.

5. 2 endo (a-diethylaminopropionylamino)-bicyclo- (2,2,1)-heptane.

6. 2 exomethyl 2 endo (diethylaminoacetamino)- bicyclo- 2,2,1 -heptane.

7. 2 endo henzylaminoacetamino) (2,2,1 -heptane.

8. 2 endo [(2 diethylaminoethyl) aminoacetamino -bicyclo (2,2,1 -heptane.

9. 2 endo (dimethylaminoacetamino) bycyclo- (2,2,1)-heptane.

10. 2 endo (isopropylaminoacetamino) bicyclo- (2,2,1)-heptane.

11. 2 (diethylaminoacetamino) bicyclo (2,2,2)- octane.

12. 2 endo [N methyl N (diethylaminoacet)- amino] -bicyclo-( 2,2,1 )-heptane.

13. 7 (diethylaminoacetamino) bicyclo- (2,2,1)- heptane.

14. 7 (diethylaminoacetamino) bicyclo (2,2,1)- heptane.

15. 2 endo (methylethylaminoacetamino) bicyclo- (2,2,1)-heptane.

16. 2 endo (di n propylaminoacetamino) -bicycle-(2,2,1 )-heptane.

17. 2 endo (ethyl n propylaminoacetamino)- bicyclo-(2,2,1 -heptane.

18. 5 endo (diethylaminoacetamino) bicyclo- (2,2,1 )-2-heptene.

- bicyclo- References Cited in the file of this patent UNITED STATES PATENTS 2,681,931 Jenkins June 22, 1954 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No... 2,926 172. February 23 1960 Werner R. Boehme et a1.

rinted specification It is hereby certified that error appears in the p id Letters oi. the above numbered patent requiring correction and that the sa Patent should readas corrected below.

n 10 line 48., for "7-(diethylaminoacetamino) read CoIum 1-(0Iiethylaminoacetamino) Si'gn-ed and sealed this. 9th day of August 1960.

(SEAL) Attest z I KARL H, AXLINE ROBERT C. WATSON Attesting Oflicer Commissioner of Patents 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS REPRESENTED BY THE GENERAL FORMULA: 